The general literature for an enantioselective synthesis for chiral intermediates and final products containing hydroxylamines, hydroxamate or hydroxyurea functionalities is quite limited. Obtainment of either desired configuration (i.e., (R) or (S)) occurs primarily by three routes, 1) resolution, 2) separation of a racemic mixture by derivatization and separation means, such as by column chromatography, or 3) by enantioselective synthesis.
For hydroxyurea containing compounds a synthesis has been described in patent application WO 91/14674, published 10.03.91 to Adams et al. which teaches obtainment of the chiral hydroxylamine, which upon appropriate work-up results in a chiral final product. This method is not, however, commercially feasible, due to excessive costs in obtaining the chiral intermediate by the processes indicated therein.
Primarily, the work in the past to achieve chiral compounds, lies in the use of nucleophilic additions to chiral nitrones. These chiral nitrones, bear various auxiliaries, (such as sugars or other chiral moieties) giving a non-racemic environment for nucleophilic addition or dipolar cycloaddition reactions. Various allylic Grignard reagents have generally been used in these reactions. For instance, Schwartz et at., Tet. Lett., 34, p 1011 (1993) employs a nucleophilic addition to a sugar based chiral nitrone for an enantioselective formation of a chiral hydroxylamine and uses a gulose based sugar and Grignard reagents as the nucleophile. To achieve a high level of enantioselectivity, co-addition of trimethylaluminum, a hazardous agent, is required.
Mancini et at., J. Org. Chem., 56, p 4246-252 (1991) also describes a chiral hydroxylamine synthesis using as a chiral auxiliary, a sugar moiety which is mannose derived. Mancini et al., requires adding an allyl Grignard reagent to the nitrone bearing sugar molecule which after reactoion with an O-trialkylsilyl reagent and treatment with an iodinating agent cyclize to an isoxazolidine compound.
Huber etal., Helv. Chim. Acta, 68, 1730 (1985) describes both the diasterioselective 1,3-dipolar cycloadditions of N-glycosylnitrones to methyl methacrylate to afford N-glycosylisoxazolidines and the diastereroselective nucleophilic addition of lithium and potassium dialkylphophites to N-glycoxylnitrones to yield N-glycosyl-N-hydroxyaminophosphonates.
The use of trimethylsulfoxonium iodide and potassium tert-butoxide (in DMSO) have previously been shown by Ng, J., Synthetic Comm., 20(8), 1193-1202 (1990), to prepare epoxides from aldehydes and ketones. Previously the most common method to prepare epoxides from aldehydes and ketones involved the use of methyloxosulfonium and methylsulfonium methylides developed by Corey et al., J. Am. Chem.Soc, 84, 867 (1962); and J. Am. Chem. Soc., 87, 1353 (1965). For an additional review of dimethylsulfoxonium methylide see Golobobov et al., Tetrahedron, 43, 2609 (1987). Holt et al., Tetrahedron Letters, 7,683-686 (1966) describe the reaction of dimethylsulphoxonium methylide with ortho-hydroxy aldehydes to yield hydroxy substiututed benzofuran derivatives as described therein.
The use of these reagents as applied to chiral nitrones for intramolecular cyclization of heterocylic rings, such as benzo[d]furan heterocycles, from a chiral mannose nitrone intermediate, as described in the present invention, is novel and suitable for large scale commercial processes.
There exists a need, in this art, to provided a highly diasteroselective synthesis for hydroxylamine intermediates which resulting product has a high optical purity and can be done is a single stage. Preferably, the resultant synthesis should also allow regeneration and recovery of the chiral auxiliary to reduce synthesis costs.